Incorporation of absorbents during extraction and/or hydration of hydrogel materials used as ophthalmic devices

ABSTRACT

Disclosed are methods for extracting leachable materials from a hydratable polymer by incorporation of an adsorbent into the solution employed to effect extraction. Suitable adsorbents are characterized as having a higher affinity for the leachable materials than either the hydratable polymer or the solvent employed in the solution. Also disclosed are sealed packages comprising an aqueous solution, an adsorbent and a hydratable polymer in the form of an ophthalmic device.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to methods for extracting leachable materialsfrom a hydratable polymer such as a xerogel material. In one embodiment,the extraction is conducted after hydration of the hydratable polymer.In another embodiment, extraction is conducted simultaneously withhydration of this polymer to a hydrogel material. In either case, theresulting hydrogel material can then be used in ophthalmic devices suchas intraocular lenses, contact lenses, etc.

In the methods of this invention, extraction procedures are simplifiedby incorporation of an adsorbent into the solution which facilitatesextraction of the leachable materials from the hydratable polymer. Whenthe extraction solution is water and the hydratable polymer is in itsxerogel form, hydration of the hydratable polymer to the hydrogelmaterial occurs simultaneously with extraction.

This invention is further directed to a sealed package forshipping/storing hydrogel materials in the form of ophthalmic deviceswhich incorporates water and an adsorbent into the package whichadsorbent effects selective retention of leachable components from theophthalmic device. These packages are particularly useful for in situconversion of a xerogel material to a hydrogel material in the form ofan ophthalmic device with concomitant extraction of the leachablecomponents from the device. When so employed, the xerogel form of theophthalmic device can be directly packaged and shipped for consumer usewhile permitting hydration and extraction to occur in situ therebyproviding for a hydrated ophthalmic device suitable for consumer use.

2. State of the Art

The preparation of hydrogel ophthalmic devices, e.g., soft contactlenses, for consumer use is a multi-step process. In addition to theimportant concerns relating to manufacturing a contact lens or otherophthalmic device which is appropriately fitted for the particularconsumer's needs, the ophthalmic device manufacturing process mustinclude process steps for removal of leachable materials from thehydratable polymer used in the device.

Specifically, soft hydrogel ophthalmic devices are prepared bypolymerizing a monomeric composition to a dry hydratable polymertypically referred to in the an as a "xerogel" or a "xerogel material".The as-prepared xerogel material typically contains leachable materialssuch as unreacted monomers and partially reacted oligomers.Contamination of the xerogel material with such monomers and oligomersis undesirable since these materials are toxic and, during use, canleach into the eye fluid causing, for example, eye irritation and otherproblems. Accordingly, the U.S. Food and Drug Administration (FDA) hasset standards relative to maximum monomer/oligomer concentration inophthalmic devices for consumer use. In order to meet these standards, aportion of the leachable materials must be removed from the polymercomposition which removal is typically achieved by several washings ofthe ophthalmic devices using water, ethanol, or other suitable solvents.When using such solvents, a portion of the leachable materials,including the unreacted monomers and partially reacted oligomers, aretransferred under a mass-transfer mechanism to the solvent which solventis subsequently discarded. This washing step is repeated until leachablecontamination in the ophthalmic device is reduced to acceptable levels.

When water is used as the washing material, the washing steps alsoresult in hydration of the hydratable polymer from its xerogel to itshydrogel form. When ethanol or other non-aqueous solvents are employedin the washing steps, then a separate hydration step is afterwardsrequired to form the final hydrogel.

After extraction/hydration, the ophthalmic device is typically insertedinto a sealed package containing an aqueous buffered solution forshipment and storage prior to consumer use. The inclusion of the aqueousbuffered solution in the package is necessary to insure againstdehydration of the hydrated ophthalmic device.

In any event, the process of effecting formation of a hydratedophthalmic device from a hydratable polymer in the form of a xerogelmaterial involves numerous extraction/hydration steps which necessarilyhinder efficient manufacture of ophthalmic devices prior to packaging ofthese devices into end use form. Additionally, the presence of leachablematerials in the discarded solvent can cause disposal problems.

In addressing this problem, the art has described methods which resultin the extraction of leachable materials to a desired level. Forexample, Kindt-Larsen, U.S. Pat. No. 5,080,839, discloses a processwherein the contact lens is placed into a cavity defined by a first anda second carrier element which both confines and maintains a properorientation for the lens. A fluid flow is then introduced through thecavity to effect flushing of the leachables from the lens which fluidflow can be repeated as necessary to effect reduction of the leachablesto a desired level. Allegedly, the use of such a fluid flow through thiscavity results in more efficient removal of the leachables from the lensand reduces the need to physical manipulate the lens while maintaining aproper orientation of the lens in the cavity.

However, notwithstanding the advantages of this method, there is acontinuing need in the art to simplify the extraction/hydration stepsrequired to form an ophthalmic device having acceptable contaminant(i.e., leachable material) concentration. In this regard, it would beparticularly advantageous if the extraction/hydration step could becoupled with a packaging step so as to provide for an overall efficientmethod for preparing and packaging an ophthalmic device for consumeruse.

SUMMARY OF THE INVENTION

This invention is based, in part, on the discovery that methods for theextraction of leachable materials from an ophthalmic device can begreatly simplified by the inclusion of an adsorbent into the extractionsolution which adsorbent effects selective retention of leachablematerials from the ophthalmic device.

Accordingly, in one of its method aspects, this invention is directed toa method for extracting leachable materials from a hydratable polymer inthe form of an ophthalmic device which method comprises:

(a) incorporating an adsorbent into an aqueous solution; and

(b) contacting the hydratable polymer with the solution produced in (a)above and maintaining said polymer in such contact under conditionssufficient to reduce the concentration of said leachable material insaid polymer.

In this embodiment, the hydratable polymer can be in its xerogel form,its hydrogel form or can be in an organic solvent swollen form whereinthe organic solvent is a hydrophilic solvent having a boiling point ofabout 40° C. and above. Such solvents are non-reactive with thehydratable polymer and, include by way of example, methanol, ethanol,ethylene glycol, glycerol, N-methyl pyrrolidone, methylene chloride,boric acid esters of polyhydric alcohols and dihydric alcohols and thelike.

This invention is also based, in part, on the discovery that thehydratable polymer can be contacted with the aqueous solution prior toincorporation of the adsorbent. Accordingly, in another of its methodaspects, this invention is directed to a method for extracting leachablematerials from a hydratable polymer in the form of an ophthalmic devicewhich method comprises:

(a) incorporating an adsorbent into an aqueous solution comprising waterand a hydratable polymer; and

(b) maintaining said polymer in said aqueous solution under conditionssufficient to reduce the concentration of said leachable material insaid polymer.

This invention is still further based, in part, on the discovery thatwhen the hydratable polymer is in its xerogel form, inclusion of such anadsorbent into the solution simultaneously effects extraction ofleachable materials from the hydratable polymer as well as hydrates thepolymer composition to its hydrogel form.

Accordingly, in another of its method aspects, this invention isdirected to a method for extracting leachable materials from ahydratable polymer in the form of an ophthalmic device and hydratingsaid polymer which method comprises:

(a) incorporating an adsorbent into an aqueous solution; and

(b) immersing a hydratable polymer in its xerogel form into the solutionproduced in (a) above and maintaining said polymer in said solutionunder conditions sufficient to reduce the concentration of saidleachable materials from said polymer and to hydrate said polymer.

The method for simultaneously extracting leachable materials from thehydratable polymer and hydrating the polymer to a hydrogel material inthe form of an ophthalmic device is particularly useful for in situconversion of the hydratable polymer from its xerogel form to itshydrogel form in a sealed package thereby facilitating overallmanufacturing and shipment procedures. In this embodiment, thisinvention is directed to a sealed package comprising an aqueoussolution, a hydratable polymer in the firm of an ophthalmic device andan adsorbent wherein said package contains sufficient solution toimmerse said polymer and further wherein said adsorbent has a higheraffinity for the leachable materials than either the hydratable polymeror the solution.

In a preferred embodiment, the adsorbent is separated from thehydratable polymer. Such separation can comprise physical separationwhere, for example, the adsorbent is physically isolated from thehydratable polymer by a permeable barrier or chemical separation where,for example, the adsorbent can comprise a second solvent non-misciblewith the first solvent (e.g., the use of methylene chloride as theadsorbent in an aqueous environment).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and FIG. 1B illustrate a sealed vial containing water, anadsorbent and a hydratable polymer in the form of an ophthalmic devicefor the in situ extraction of leachables from the polymer and hydratingthe polymer to a hydrogel material wherein the packaging is suitable forshipment and storage of the ophthalmic device to the consumer.

FIG. 2A and FIG. 2B illustrate one embodiment of a sealed blisterpackage in different positions which package contains water, anadsorbent and a hydratable polymer in the form of an ophthalmic devicefor the in situ extraction of leachables from the polymer and hydratingthe polymer to a hydrogel material wherein the packaging is suitable forshipment and storage of the ophthalmic device to the consumer.

FIG. 3A and FIG. 3B illustrate another embodiment of a sealed blisterpackage in different positions which package contains water, anadsorbent and a hydratable polymer in the form of an ophthalmic devicefor the in situ extraction of leachables from the polymer and hydratingthe polymer to a hydrogel material wherein the packaging is suitable forshipment and storage of the ophthalmic device to the consumer.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to methods for extracting leachable materialsfrom a hydratable polymer by incorporation of an adsorbent into thesolution employed to effect extraction. However, prior to describingthis invention in further detail, the following terms will first bedefined.

Definitions

As used herein, the following terms have the meanings set forth below.If not defined, the terms have their art recognized meanings.

The term "leachable materials" refer to materials contained in ahydratable polymer which can be extracted from the polymer into asolvent such as water or an organic solvent such as ethanol. Typically,extraction of the leachable material into the solvent system is achievedby mass balance principles wherein an equilibrium concentration of theleachable material is achieved between the solvent and hydratablepolymer phases. In practice, the leachable materials in the hydratablepolymer are typically unreacted monomer used to prepare the hydratablepolymer and/or partially reacted oligomers which have a degree of watersolubility and are small enough to migrate through the polymer phaseinto the solvent phase. Partially reacted oligomers are preferablycharacterized as having no more than about 50 monomer units and morepreferably as having a molecular weight of less than about 5,000.

The term "hydratable polymer" refers to polymer compositions which,after polymer formation, are hydratable when treated with water and,accordingly, can incorporate water into the polymeric matrix withoutitself dissolving in water. Hydratable polymers include such polymercompositions in either their non-hydrated or hydrated state. Hydratablepolymer compositions include polymers prepared in the presence of anon-aqueous solvent or post-treated with a non-aqueous solvent whereinthe non-aqueous solvent can be exchanged with water.

Preferably, the hydratable polymers are capable of incorporating atleast about 10 weight percent water, and preferably from about 10 toabout 95 weight percent water, into the polymer composition based on thetotal weight of the polymer composition. As known per se in the art,hydratable polymers are prepared by incorporation of one or morehydrophilic monomers into the polymer composition.

The term "dry polymer composition" refers to a hydratable polymercomposition in its non-hydrated state which is typically formed bypolymerization of the monomer composition in the absence of added waterwherein any water in the resulting polymer composition is usually due totraces of moisture present in one or more of the reagents used toprepare the polymer composition. Such moisture is typically less than 1weight percent of the total polymer composition and preferably less than0.1 weight percent. Such compositions are also referred to as "xerogelpolymer compositions" or "hydratable polymer in a xerogel form".

The term "adsorbent" refers to any material having a greater affinityfor at least one of the leachable materials as compared to both thesolution employed to remove the leachable materials and the hydratablepolymer. In this regard, the term "adsorbent" is not intended to implyany physical or chemical mechanism for effecting affinity of theleachable material to the adsorbent and any adsorbent which possessessuch affinity is suitable for use herein regardless of whether theaffinity is achieved by adsorption, absorption, ionic interactions,covalent binding, or any other mechanism.

Suitable adsorbents for use herein include, by way of example, activatedcarbon, silica gel, an organic solvent forming a two phase system withwater such as methylene chloride, chloroform, and the like. Combinationof adsorbents can be used to effect reduction of the leachable materialsto suitable levels. In a preferred embodiment, an adsorbent material orcombination of adsorbent materials is employed which, when used insufficient amounts, will reduce the amount of leachable materials in thehydratable polymer after treatment to a level of less than about 10 ppm.

The term "aqueous solution" refers to solutions based primarily on waterbut which can comprise up to about 5 weight percent of a miscibleorganic solvent. It is contemplated that the inclusion of such amiscible organic solvent in the aqueous solution can facilitate theremoval of the leachable materials from the polymer composition. Insofaras the adsorbent material can adhere the organic solvent, an aqueoussolution employing such a miscible organic solvent is preferablycontacted with the hydratable polymer prior to addition of the adsorbentto the solution.

Suitable miscible organic solvents are those which will not chemicallyreact with or solubilize to any significant extent the hydratablepolymer in either its xerogel or hydrogel forms. Suitable solvents arewell known in the art and include, by way of example, water, methanol,ethanol, ethylene glycol, glycerol, N-methyl pyrrolidone, methylenechloride, boric acid esters of polyhydric alcohols and dihydric alcoholsand the like. Suitable polyhydric alcohols and dihydric alcohols aredisclosed in U.S. Pat. Nos. 4,495,313 and 5,039,459 both of which areincorporated herein by reference in their entirety.

The term "hydrophilic ethylenically unsaturated monomer" refers tomonomers which when incorporated in sufficient amounts into a polymerwill render the polymer hydratable, i.e., will permit the polymer toabsorb at least 10% water. Such monomers are well known in the art andthe use of any such monomer is not critical. Suitable hydrophilicethylenically unsaturated monomers suitable for use herein include, byway of example only, hydroxy lower alkyl acrylates or methacrylates,hydroxy lower alkoxy lower alkyl acrylates or methacrylates, and alkoxylower alkyl acrylates or methacrylates. "Lower alkyl" or "lower alkoxy"is herein defined to mean an alkyl or alkoxy having from 1 to 6 carbonatoms. Specific hydrophilic monomers include hydroxyethyl methacrylate(HEMA), hydroxyethylacrylate, hydroxypropyl methacrylate, hydroxypropylacrylate, butanediol monomethacrylate monoacrylate, glyceryl acrylate,glyceryl methacrylate, vinylpyrrolidone, N,N-dimethylacrylamide, and thelike. The hydroxyalkyl acrylates and methacrylate, particularly2-hydroxyethyl methacrylate are generally preferred.

The term "ethylenically unsaturated monomers free of hydrophilicfunctionality" refers to comonomers conventionally employed incombination with a hydrophilic ethylenically unsaturated hydrophilicmonomer in the preparation of hydratable polymers suitable for use incontact lenses which monomers are free of hydrophilic functionality.Such monomers include styrene, acrylates or methacrylates such as methylmethacrylate, ethyl acrylate, isopropyl acrylate, propyl acrylate, butylacrylate, sec-butyl acrylate, pentyl acrylate, 2-ethylhexyl acrylate,methyl methacrylate, ethyl methacrylate, propyl methacrylate, isopropylmethacrylate, butyl methacrylate, sec-butyl methacrylate, pentylmethacrylate, cyclohexyl methacrylate and fluorinated acrylates andmethacrylates such as trifluoromethyl methacrylate, trifluoromethylacrylate, 2',2', 2'-trifluoroethyl methacrylate, 2',2',2'-trifluoroethylacrylate, 1,1,1,3,3,3-hexafluoroisopropyl methacrylate, etc., arylacrylates and methacrylates such as phenyl acrylate, phenylmethacrylate, etc. Other suitable monomers include allyl or aryl vinylethers such as ethyl vinyl ether, phenyl vinyl ether, and the like.

Methods

The methods of this invention effect removal of leachable materials fromhydratable polymers by incorporating an adsorbent into an aqueoussolution and contacting the hydratable polymer with this solution underconditions sufficient to reduce the concentration of said leachablematerial in said polymer.

The aqueous solution, including any miscible organic solvent employedtherein, should be compatible with the hydratable polymer to the extentthat the solution will not (1) degrade (e.g., dissolve) the hydratablepolymer; (2) chemically react with the hydratable polymer; and (3) alterits physical or chemical properties so that the hydratable polymer is nolonger suitable for use as an ophthalmic device. The aqueous solutioncan be limited to contain only water, but preferably, aqueous solutioncan comprise additional components such as buffers, salts, etc.,suitable for use in contact lens wear. A particularly preferred solutionfor use herein is an aqueous saline solution buffered to a pH of fromabout 6 to 8, more preferably from about 6.2 to 7.7 and still morepreferably from about 6.5 to 7.5. The particular buffers and saltsemployed are not critical.

An adsorbent is then incorporated into the selected solution. Typically,the amount of adsorbent employed is sufficient for the intended purpose,i.e., to remove leachable materials from the selected solution and,hence, from the hydratable polymer. In a preferred embodiment, at leastabout 1 gram of adsorbent is employed per gram of hydratable polymer tobe treated. The upper limit on the amount of adsorbent is governedsolely by physical constraints and costs considerations. Typically,however, no more than about 5 grams of adsorbent is employed per gram ofhydratable polymer. The exact amount of adsorbent employed is governedby the relative affinity of the leachable materials to the adsorbent,the amount of leachable materials to be removed, etc. Such factors canbe readily determined by the skilled artisan.

A hydratable polymer, preferably in its xerogel form, is then contactedwith the solution comprising the adsorbent produced as above or,alternatively, with the aqueous solution prior to addition of theadsorbent. However, hydratable polymers, including those in theirhydrogel forms or in an organic solvent swollen form can also beemployed in the methods described herein to effect removal of leachablematerials therefrom.

Contact of the polymer with this solution is then maintained underconditions sufficient to reduce the concentration of said leachablematerial from said polymer. Preferably, contact of the hydratablepolymer with this solution is achieved by immersing the polymer in thesolution. However, other embodiments where the polymer contacts thesolution can also be employed and include, by way of example, where thesolution wicks the polymer; where the polymer is contacted with abibulous material containing said solution; and the like.

The contacting conditions employed are not critical and the contactconditions are selected to be sufficient for the intended purpose, i.e.,to remove leachable materials from the selected solution. Preferably,however, the hydratable polymer is contacted with this solution at atemperature of from above about 0° C. to about 150° C. for a period offrom about 10 to about 60 minutes. In a particularly preferredembodiment, elevated temperatures, e.g., from about 40° C. to about 150°C., can be employed to accelerate the extraction process.

Preferably, the adsorbent employed is separated from the hydratablepolymer so as to avoid contamination of the polymer with the adsorbentwhich can be troublesome if the adsorbent is in the form of fineparticles. Such separation can be achieved by conventional means such asby incorporating the adsorbent into a solution permeable membrane,physically entrapping the adsorbent into the walls of the container, andthe like.

The hydratable polymer employed is not critical provided that it canincorporate at least about 10 weight percent water upon hydration. As iswell known in the art, such hydratable polymers are formed by use of ahydrophilic ethylenically unsaturated monomer during polymer formation.Such monomers are employed in a range from about 1 to 100 weight percentbased on the total amount of monomer with the balance beingethylenically unsaturated monomer(s) free of hydrophilic functionality.The specific amounts of each monomer selected are dependent upon thedesired properties for the resulting polymer composition including anability of the polymer composition to incorporate at least about 10weight percent water which, in turn, depends upon the relativehydrophilicity of the hydrophilic ethylenically unsaturated monomer aswell as the relative hydrophilicity of any other comonomers and therelative amounts of each in the resulting polymer. Such factors arereadily ascertainable by the skilled artisan. Due to this ability toincorporate water, the resulting polymer composition is often referredto as a "hydrogel" or "hydrogel material".

While hydrogels derived from a single monomer can be used, copolymeric,terpolymeric, etc. hydrogels are typically employed because the use ofmore than one monomer provides a ready vehicle to tailor a broad rangeof properties in the final product for its intended use. Examples ofcopolymeric or higher hydrogels include the polymer compositions setforth in the table below:

    ______________________________________    Monomer A             Monomer B   Monomer C   Monomer D    ______________________________________    MMA      DMA         EGDMA       --    MMA      DMA         EGDMA       --    HEMA     NVP         MAA         --    MMA      NVP         AMA         --    MMA      GMA         EGDMA       --    HEMA     DMA         MMA         TMPTMA    HEMA     DMA         MMA         TMPTMA    HEMA     EGDMA       --          --    HEMA     MMA         NVP         DVB    ______________________________________     AMA = allyl methacrylate     DMA = dimethylacrylamide     DVB = divinyl benzene     EGDMA = ethylene glycol dimethylacrylate     GMA = glyceryl methacrylate     HEMA = hydroxyethyl methacrylate     MMA = methylmethacrylate     NVP = Nvinylpyrrolidone     TMPTMA = trimethylolpropane trimethacrylate

Commercially available copolymers, terpolymers, etc. suitable for useherein include tetrafilcon A, polymacon, bufilcon A, crofilcon A,surfilcon A, perfilcon A, netrafilcon A, and the like.

Also, as is apparent from the above, the hydratable polymer canoptionally be cross-linked.

Figures

Certain aspects of this invention can be better understood by referenceto the attached figures. Specifically, in FIG. 1A and FIG. 1B, a vial 10comprising a glass container 11 and cap 12 which is fitted ontocontainer 11 by conventional means, e.g., a screw cap which mates withthe opening of container 11 (not shown), to form a water proof seal.Glass container 11 contains a selected solution 13 which, in thisembodiment, is water, and a hydratable polymer 14 in the form of acontact lens. A water permeable membrane 15 shown in the cut awayportion of cap 2 contains adsorbent therein. Extraction of leachablematerials from hydratable polymer 14 and selected solution 13 by theadsorbent is achieved by inverting closed vial 10 thereby contacting theadsorbent with the selected solution 13 as illustrated in FIG. 1B. Theadsorbent's greater affinity for the leachable material as compared tohydratable polymer 14 and selected solution 13 results in a portion ofthe leachable material becoming bound to the adsorbent. The amount ofleachable material removed by the adsorbent is dependent upon the degreeof leachable material contamination in the hydratable polymer, therelative affinity of the adsorbent for this material and the amount ofadsorbent employed. Each of these factors is well within the skill ofthe art.

In one embodiment, after inverting vial 10, the vial contents aresterilized which not only kills any microorganisms contaminating thevial but also will accelerate the removal of leachable materials by theadsorbent.

In FIG. 2A and FIG. 2B, blister package 20 comprises a well 21 whichcontains an aqueous solution 22, a hydratable polymer 23 in the form ofa contact lens, a water permeable membrane 24 and an adsorbent 25. Inthe embodiment depicted in FIG. 2A, hydratable polymer 23 is immersed inthe aqueous solution 22 but neither polymer 23 nor aqueous solution 22contacts the adsorbent 25. As shown in FIG. 2B, by inverting blisterpackage 20, aqueous solution 22, and hence polymer 23, are now incommunication with adsorbent 25. In a preferred embodiment, blisterpackage 20 is packaged in the position shown in FIG. 2A and issterilized in the position shown in FIG. 2B.

In one embodiment, blister package 20 is configured to be sufficientlytransparent to permit inspection and measurement of the hydratablepolymer 23 within the sealed package.

FIG. 3A and FIG. 3B illustrate a different configuration for a blisterpackage 30 which comprises a well 31 containing an aqueous solution 32,a hydratable polymer 33 in the form of a contact lens, a water permeablemembrane 34 and an adsorbent 35. In the embodiments depicted in FIG. 3Aand FIG. 3B, hydratable polymer 33 is immersed in the aqueous solution32 which contacts the adsorbent 35 in both instances. In a preferredembodiment, blister package 30 is packaged in the position shown in FIG.3A and is sterilized in the position shown in FIG. 3B.

In another embodiment, a female mold half as described in FIG. 6b ofU.S. Pat. No. 4,955,580 can be used to prepare a contact lens from ahydratable polymer in its xerogel form which mold portion can be used inpackaging and shipping the contact lens. The closure element illustratedin FIG. 6a of U.S. Pat. No. 4,955,580 can be used with the female moldhalf so as to form a water tight seal for packaging and storage. Thedisclosure of U.S. Pat. No. 4,955,580 is incorporated herein byreference in its entirety.

The following examples illustrate certain embodiments of the inventionand are not meant to limit the scope of the claims in any way.

In the following examples, the following abbreviations have the meaningsset forth below. If not defined, the abbreviation has its art recognizedmeaning.

cm=centimeter

DMA=dimethyl acrylamide

GMA=glyceryl methacrylate

GPC=gel permeation chromatography

HEMA=hydroxyethyl methacrylate

HPLC=high performance liquid chromatography

kg=kilogram

mL=milliliters

MMA=methyl methacrylate

NVP=N-vinyl pyrrolidone

psi=pounds per square inch

μM=microns or micrometers

EXAMPLES

Example 1 below sets forth a simple procedure for evaluating whether acandidate material is a suitable adsorbent for the purposes of thisinvention. Example 2 demonstrates the correlation between level ofleachable material contamination in the hydratable polymer and the areaunder the HPLC peaks. Examples 3 and 4 illustrate methods for usingadsorbents for the purpose of removing impurities from polymercompositions. Examples 5 and 6 illustrate that the methods describedherein can be employed in combination with packaging of a contact lensmade from a hydratable monomer so as to effect both hydration of thelens and removal of the leachable materials. Example 7 illustrates theadvantage of heating during the adsorption process so as to reduce thelevel of leachable materials retained in the hydratable polymer aftertreatment. Example 8 demonstrates the efficacy of the described methods.

Example 1

A measured amount of a candidate adsorbent (0.05 g) was placed directlyinto a glass vial and a freshly demolded hydratable polymer in the formof a contact lens in the xerogel state, made from a copolymer of N-vinylpyrrolidone and methyl methacrylate using allyl methacrylate as across-linking agent, was also placed into the vial together with 2 mL ofdeionized water. The vial was sealed and put through an autoclave cycleof 121° C. at 15 psi (1.0546 kg per cm²) for 30 minutes. The water fromthe vial was then filtered through a 0.2 μm filter and analyzed forimpurities by HPLC.

HPLC analysis of the filtered solution is employed because any leachablematerials remaining in the filtered solution reflects the inability ofthe adsorbent to remove these materials from the solution. Accordingly,integration of the HPLC peaks correlates the ability of the adsorbent toadhere leachable materials thereby removing these materials from theaqueous solution and hence the hydratable polymer. Lower HPLC peakintegration values correspond to better adsorbent ability.

The results of this analysis using different candidate adsorbents areset forth in Table 1 below.

                  TABLE 1    ______________________________________                         HPLC ANALYSIS    ADSORBENT            PEAK AREA    ______________________________________    No Adsorbent         4,800    Activated Carbon Type RO-0.8                         0    Activated Carbon Type 12/20#                         3    Activated Carbon Type 4/14#                         10    Activated Carbon Type G-60100#                         0    Eudragit L100-55     6    Eudragit S100        4    Molecular Sieves 3A  4,900    Silica Gel           1,600    ______________________________________     Activated Carbon Types RO0.8, 12/20#, 4/14#, and G60100# can be obtained     from Aldrich Chemical Company, Milwaukee, Wisconsin. Eudragit L10055 and     S100 are acrylic polymers available from Rohm Pharma, Weiterstadt,     Germany.

The above data demonstrates that activated carbon effectively removesimpurities from the aqueous solution, that silica gel also removedimpurities from the aqueous solution, albeit less efficiently thanactivated carbon, and that molecular sieves 3A do not.

In the absence of an adsorbent, the amount of impurities in the water isdictated by an equilibrium balance between the polymer and the water. Inturn, adherence of the impurities to the adsorbent effectively shiftsthis equilibrium balance resulting in the impurities in essence being"pulled" from the polymer composition through the water onto theadsorbent. Such a process provides an efficient means to removeimpurities from the polymer composition.

Example 2

This example demonstrates the correlation between integrated HPLC peakareas and the level of leachable material contamination in thehydratable polymer. Specifically, calibration curve for the HPLCanalysis was developed for the N-vinyl pyrrolidone and methylmethacrylate monomers that could be present in the polymerizedcopolymers of N-vinyl pyrrolidone/methyl methacrylate. The relationshipbetween HPLC peak area and quantity of monomer in water was determinedby adding known amount of each of these materials to water. Thecorrelation was determined as follows:

    ______________________________________    HPLC Calibration    N-Vinyl Pyrrolidone                     Methyl Methacrylate    ppm   HPLC Peak Area*                         ppm      HPLC Peak Area*    ______________________________________    0.05     0           0.05      9.4    0.10   5.4           0.10      8.3    0.20   7.8           0.20      7.8    0.40   24.5          0.40     10.6    0.80   33.6          0.80     33.7    1.60   54.3          1.60     26.2    3.20  106.0          3.30     49.7    6.40  218.4          6.60     87.8    12.9  460.2          13.1     170.0    25.8  964.0          26.3     345    51.6  2550           52.6     728    103.2 4096           105.3    1417    ______________________________________     *Arbitrary units full scale; analysis made on a C8 column using     acetonitrile/water under reverse flow conditions and detected by UV     (ultraviolet) at 254 nanometers

The above correlation data permits one skilled in the art to readilyassess the amount of monomer (in ppm) present in the solution based onintegration of the HPLC peak corresponding to these monomers. Similarcorrelation curves could readily be prepared for other monomers.

Example 3

The purpose of this example is to demonstrate the use of a waterpermeable membrane to separate the adsorbent from the hydratablepolymer. The water permeable membrane is capable of retaining theadsorbent therein but permits transport of the aqueous solution thereacross.

Specifically, an envelope was fashioned from a 0.2 μm nylon membrane byheat sealing and a small amount of an adsorbent, 0.03 grams of activatedcarbon (Norit RO-0.8, available from Aldrich Chemical Company,Milwaukee, Wis., USA) was then enclosed and the envelope was heat sealedto fully contain the adsorbent. The filled envelope was then placed intoa glass lens vial together with 10 freshly demolded dry lenses, made ofa copolymer of N-vinyl pyrrolidone and methyl methacrylate, and a 2 mLaliquot of deionized water was added. The vial was sealed with a rubberclosure and crimp seal and was then subjected to an autoclave cycle of121° C. at 15 psi (1.0546 kg per cm²) for 30 minutes. After autoclaving,the water from the vial was analyzed by HPLC and GPC for the presence ofimpurities and none were found.

Example 4

The purpose of this example is to evaluate the ability of an adsorbentto remove impurities from different polymer compositions. Accordingly,four different polymer compositions were treated in the manner describedabove for Example 1 and the recovered aqueous solution evaluated for thepresence of impurities by HPLC. The results of this evaluation are setforth in Table 2 below.

                  TABLE 2    ______________________________________    LENS      HPLC PEAK AREA FOR MAIN PEAK    POLYMER   NO ADSORBENT  WITH ADSORBENT*    ______________________________________    NVP/MMA   5000          0    GMA/MMA    592          9    HEMA      7262          0    DMA/MMA    654          4    ______________________________________     *Adsorbent in this case was activated Carbon Norit RO0.8

The results of the above example illustrate that an adsorbent can beused to remove leachable impurities from several different polymercompositions.

Example 5

In a study using polypropylene "blister" packages, the adsorbent wasretained between the lidding stock and a membrane wherein the membranewas heat sealed to the lidding stock. Such a device is illustrated inFIG. 2A and FIG. 2B. A freshly demolded lens of the type used in Example2 above was placed into the well defined by the blister package and 2 mLof water or saline was added as shown in FIG. 2A. The blister was thensealed with the lidding stock holding the adsorbent with the adsorbentcovering the well of the blister.

The blister package was then placed inverted into an autoclave andsterilized at 121° C. at 15 psi (1.0546 kg per cm²) for 30 minutes asshown in FIG. 2B. Several trials with different adsorbents and lenstypes were analyzed in this example and the results are set forth inTable 3 below:

                  TABLE 3    ______________________________________                        HPLC PEAK AREA    ADSORBENT           FOR MAIN PEAKS    ______________________________________    No Adsorbent        5,600    Activated Carbon Type RO-0.8                         7    Activated Carbon Type 12/20#                        370    Activated Carbon Type 4/14#                        57    Eudragit L100-55    58    ______________________________________

The above example illustrates that the methods of this invention aresuitable for removing leachable impurities from an ophthalmic deviceduring storage/shipment of this device.

Example 6

A contact lens was prepared in a mold system as per U.S. Pat. No.5,036,971 wherein the male mold half was removed after dry lenspreparation, leaving the dry lens only in the female half of the mold.An aliquot of saline solution is added to the mold and the mold is thencovered with a lidding stock as per Example 5 above so that the membranecontaining an adsorbent covers the well of the female mold. This lenswas allowed to hydrate in the packaging solution and then the packagedlens was autoclaved in the inverted portion.

The above example illustrates that the methods of this invention can beincorporated with the manufacturing process so as to simplifymanufacturing of the lens, removal of contaminants and shipment forconsumer use into a single overall process.

Example 7

The purpose of this example is to illustrate the advantage of heatingthe adsorbent/hydratable polymer/aqueous solution to enhance adsorbencyof the leachable material onto the adsorbent.

In this example, an adsorbent (0.05 g) was added to individual glassvials. A contact lens made of a hydratable polymer similar to that ofExample 1 above was added to each vial along with 2 mL of water. Eachsample of adsorbent was conducted in duplicate so as to provide twovials containing the same adsorbent, the same type of contact lens andthe same amount of water. The vials were sealed and the first vialcontaining the same adsorbent was maintained at room temperature for 30minutes whereas the second vial was autoclaved at 121° C. for 30minutes. After, yards, the solution in each of the vials was analyzed byHPLC and the amount of leachable material remaining in the solutiondetermined by integration of the HPLC peak area. The results of thisanalysis are set forth in Table 4 below:

                  TABLE 4    ______________________________________                HPLC Peak Area*                               HPLC Peak Area*    Adsorbent   Room Temperature                               121° C.    ______________________________________    Carbon 12-20                11               2.8    Carbon RO 0.8                 3              0    Carbon 4-14 32             10    Eudragit L100-55                559            23    No Adsorbent                Not Done       5003    No Lens     Not Done        0    ______________________________________     *Arbitrary units full scale

The above results demonstrate that more efficient removable of leachablematerials by the adsorbent is achieved at higher temperatures asevidenced by the reduction of the HPLC peak area.

Example 8

In order to demonstrate that the adsorbent removes leachable materialfrom the aqueous solution in which the lenses have been placed and,hence, from the hydratable polymer itself, the following experiment wasconducted.

Ten (10) separate lenses obtained from a hydratable polymer similar tothat of Example 1 above were separately extracted in vials in thepresence of activated charcoal type 12/20#, in a manner as alsodescribed in Example 1. After this extraction and hydration, each of thelenses were removed from each of the vials, rinsed quickly withdeionised water and all placed into one vial. An aliquot of deionisedwater was then added to this vial and the vial sealed and autoclaved.The solution from the vial was then analyzed using HPLC. The quantity ofextractable material measured corresponded to less than 5 ppm ofmaterial per lens. This compares to values of more than 100 ppmtypically obtained for single lenses similarly extracted in the absenceof an adsorbent.

The above data demonstrates that the extraction methods of thisinvention effectively remove leachable material from the hydratablepolymers which leachable material is also removed from the aqueoussolution by the adsorbent used in these methods.

What is claimed is:
 1. A method for extracting unreacted monomers andpartially reacted oligomers from a hydratable xerogel polymer containingsaid monomers and oligomers wherein said polymer after hydration is inthe form of an ophthalmic device which method comprises:(a)incorporating an adsorbent into an aqueous solution wherein saidabsorbent is selected from the group consisting of activated carbon,silica gel and an organic solvent forming a two-phase system with water;and (b) contacting said hydratable xerogel polymer, prior to hydration,with the solution produced in (a) above and maintaining said polymer insuch contact under conditions sufficient to reduce the concentration ofsaid monomers and oligomers in said polymer.
 2. The method according toclaim 1 wherein said adsorbent is separated from said hydratablepolymer.
 3. The method according to claim 2 wherein said separation ofthe adsorbent from said hydratable polymer is achieved by a waterpermeable membrane.
 4. The method according to claim 1 wherein saidaqueous solution comprises up to about 5 weight percent of a miscibleorganic solvent.
 5. The method according to claim 1 wherein said aqueoussolution is a saline solution buffered to a pH of from 6 to
 8. 6. Themethod according to claim 1 wherein the amount of monomers and oligomersin the hydratable xerogel polymer is reduced to less than about 10 ppm.7. A method for extracting unreacted monomers and partially reactedoligomers from a hydratable xerogel polymer containing said monomers andoligomers and hydrating said polymer wherein said polymer, andhydration, is in the form of an ophthalmic device which methodcomprises:(a) incorporating an absorbent into an aqueous solutionwherein said absorbent is selected from the group consisting ofactivated carbon, silica gel and an organic solvent forming a two-phasesystem with water; and (b) immersing a hydratable polymer in its xerogelform and prior to hydration thereof into the solution produced in (a)above and maintaining said polymer in said solution under conditionssufficient to reduce the concentration of said monomers and oligomersfrom said polymer and to hydrate said polymer.
 8. The method accordingto claim 7 wherein said adsorbent is separated from said hydratablepolymer.
 9. The method according to claim 8 wherein said separation ofthe adsorbent from said hydratable polymer is achieved by a waterpermeable membrane.
 10. The method according to claim 7 wherein saidaqueous solution comprises up to about 5 weight percent of a miscibleorganic solvent.
 11. The method according to claim 7 wherein saidaqueous solution is a saline solution buffered to a pH of from 6 to 8.12. The method according to claim 7 wherein the amount of said monomersand oligomers in the hydratable polymer is reduced to less than about 10ppm.
 13. A method for extracting unreacted monomers and partiallyreacted oligomers from a hydratable xerogel polymer containing saidmonomers and oligomers wherein said polymer, after hydration, is in theform of an ophthalmic device which method comprises:(a) incorporating anadsorbent into an aqueous solution comprising water and a hydratablepolymer wherein said polymer, before addition to said water, is in itsnon-hydrated state and further wherein said absorbent is selected fromthe group consisting of activated carbon, silica gel and a organicsolvent forming a two-phase system with water; and (b) maintaining saidpolymer in said aqueous solution under conditions sufficient to reducethe concentration of said monomers and oligomers in said polymer. 14.The method according to claim 13 wherein said adsorbent is separatedfrom said hydratable polymer.
 15. The method according to claim 14wherein said separation of the adsorbent from said hydratable polymer isachieved by a water permeable membrane.
 16. The method according toclaim 13 wherein said aqueous solution comprises up to about 5 weightpercent of a miscible organic solvent.
 17. The method according to claim13 wherein said aqueous solution is a saline solution buffered to a pHof from 6 to
 8. 18. The method according to claim 13 wherein the amountof said monomers and oligomers in the hydratable polymer is reduced toless than about 10 ppm.
 19. A sealed package comprising an aqueoussolution, a hydratable polymer, initially a xerogel in its non-hydratedstate which after hydration is in the form of an ophthalmic device,which polymer contains unreacted monomers and partially reacted oligomercontaminants and an adsorbent wherein said package contains sufficientsolution to immerse said polymer and further wherein said adsorbent hasa higher affinity for said monomer and oligomers than either saidpolymer or the solution and still further wherein said adsorbent isselected from the group consisting of activated carbon, silica gel andan organic solvent forming a two-phase system with water.
 20. The sealedpackage according to claim 19 wherein said adsorbent is separated fromsaid hydratable polymer.
 21. The sealed package according to claim 20wherein said separation of the adsorbent from said hydratable polymer isachieved by a water permeable membrane.
 22. The sealed package accordingto claim 19 wherein said aqueous solution comprises up to about 5 weightpercent of a miscible organic solvent.
 23. The sealed package accordingto claim 19 wherein said aqueous solution is a saline buffered to a pHof from 6 to 8.